Basic research in biological rhythms can be related to affective illness with respect to (1) the inherent cyclicity of the illness (itself a type of biological rhythm) and (2) the involvement of disturbed circadian rhythms (24-hour cycles) in its pathophysiology. This project is designed to explore these connections by interrelating behavioral, physiological and biochemical changes observed (1) through the cycle of the illness, and (2) through the course of the 24-hour day. Results to date indicate (1) in depression the timing of circadian rhythms is abnormally early (phase-advanced) relative to the day-night cycle; (2) normals' sleep, temperature patterns and neuroendocrine function can be made to resemble that of depressives by shifting their sleep period 6 hours later than usual; (3) some depressives' circadian rhythm phase-advance and mood disturbances can be temporarily corrected by shifting their sleep period 6 hours earlier than usual; (4) animal studies in our laboratory indicate that the two major classes of drugs which are used to treat depression may act by slowing the intrinsic rhythm of circadian pacemakers causing a corrective delay in depressives' abnormally advanced circadian rhythms, (5) in mania the 24-hour sleep-wake cycle lengthens dramatically to 48 hours and escapes from its normal 1:1 mode of coupling to the day-night cycle; (6) the retinohypothalamic tract, which mediates the synchronizing effects of external time cues on circadian pacemakers in the hypothalamus is intact in all manic-depressives studied to date.